Otitis media (OM) is the most common disease for which children receive medical care in the United States. Complications and sequelae of OM contribute significantly to pediatric morbidity and impose a large economic burden on society. Despite these costs, persistent OM remains refractory to conventional medical treatment and disease pathogenesis is not well understood. This proposal requests 5 years of support for an existing research program focused on OM pathogenesis with the overall goal of designing rational interventions to abort or moderate that process. The program includes four projects and two supporting core units (Administration and Biostatistics). An understanding of middle ear (ME) pressure regulation in health and disease is the main theme underlying the four Projects. In that regard, clinical and experimental evidences support a central role for imbalances in ME pressure regulation as: an initiator of the disease process, a pathophysiological consequence of OM caused by other etiologies, and a promoter of disease persistence. Adequate pressure regulation requires maintaining a dynamic balance between the ME gas volume depleted by diffusive exchange and the gas volume supplied during openings of the Eustachian tube (ET). These two components of ME pressure regulation are quantitatively defined in experiments conducted under Projects of this Program. From these data, current mathematical models of ME pressure regulation will be refined and prognostic tests of dysregulation will be developed and evaluated in the ME pressure regulation will be refined and prognostic tests of dysregulation will be developed and evaluated in the clinical setting. The biochemical and pathophysiological mechanisms by which demand-supply imbalances provoke ME mucosal inflammation and OM are examined. The overall goals of that project are to define signal transduction pathways and to identify pathway components that could represent targets for pharmacological intervention. A clinical trial evaluates a promising OM treatment strategy based on the predictions of a model of disease pathogenesis that synthesizes the results of earlier studies conducted under this Program. While primarily an efficacy trial of repeated ME inflation for treatment of OM, that study also represents a formal test of the predictive accuracy of the underlying model. Successful completion of these Projects will provide a better understanding of OM pathogenesis, develop prognostic tests of ME health, and define rational intervention strategies for continued study in the clinical setting.